Chemotherapy and radiation treatments for cancer or other conditions can cause prolonged or permanent infertility. This is a significant human health concern because over 75,000 people under the age of 40 In the United States are diagnosed with cancer each year and most are cured. Adult men have the option to cryopreserve semen with sperm prior to gonadotoxic. This option is not available to prepubertal boys or adult male survivors who did not save a semen sample before treatment. For these patients, there are several stem cell technologies in the research pipeline that may preserve or restore fertility. Thi program project will generate pre-clinical radiation- and chemotherapy-induced models of male infertility in rhesus macaques that are relevant to human testis anatomy, physiology and pubertal development. The overall objective is to examine the long-term impacts of pre-pubertal chemotherapy and radiation exposure on stem cells and spermatogenesis and determine the potential of stem cell therapies to preserve and/or restore fertility. Proiect I (OnA/ig) will evalate the potential of spermatogonia! stem cell (SSC) transplantation and testicular tissue grafting or organ culture to regenerate spermatogenesis and/or produce functional sperm in monkeys treated with gonadotoxic agents during childhood. Proiect II (Clark/Byrne) will derive animal-specific induced pluripotent stem cells (IPSCs) and differentiate them into transplantable germline stem cells with autologous transplantation into chemo- and radiation-treated recipients. Proiect III (Meistrich/Shettv) will develop novel hormone suppression strategies to stimulate spermatogenesis from endogenous and/or transplanted SSCs after exposure to gonadotoxic agents. The Administrative Core A will coordinate communication and collegial interaction between project sites, transfer of biological specimens and data and report progress to NIH. Transplant Core B will provide high quality disease free rhesus macaques of the appropriate ages, generate irradiated and chemotherapy-treated models of male infertility and provide the expertise for germ cell transplantation into mice and monkeys. Each project site brings unique knowledge, expertise and resources to the program that are not available in composite at any ofthe individual sites or anywhere else in the country. Collectively, the project leaders will generate a substantial body of pre-clinical data on the feasibility of stem cell-based methods for preserving and/or restoring fertility of patients receiving gonadotoxic therapies. RELEVANCE (See instructions): There are currently no options to preserve the fertility of male cancer patient who are not producing sperm. Several academic centers in the US and abroad are actively freezing testicular tissue for cancer patients in anticipation that new stem cell technologies will be available in the future to restore their fertility. Pre-clinical studies are critically needed t test the safety and feasibility of experimental stem cell technologies so that they can be responsibly translated to the clinic.